Process for the production of basically reacting pharmaceuticals

ABSTRACT

WHEREIN R1 AND R2 TAKEN INDIVIDUALLY ARE HYDROGEN, LOWER ALKYL, PHENYL AND PHENYL ALKYL HAVING 1-5 C ATOMS IN THE ALKYLENE GROUP AND R1 AND R2 TAKEN TOGETHER IS A DIVALENT RADICAL FORMING A 5 TO 7 MEMBERED HETEROCYCLIC RING WITH THE NITROGEN ATOM SHOWN SELECTED FROM THE GROUP CONSISTING OF ALKYLENE, AZA-ALKYLENE AND OXA-ALKYLENE TO IMPROVE THE SOLUBILITY OF THE PHARMACEUTICAL SUBSTANCE IN SAID SOLVENT SYSTEM.   R1-N(-R2)-SO3H   A METHOD OF FORMING STABLE SOLUTIONS OF AT LEAST ONE PHARMACEUTICAL SUBSTANCE CONTAINING A BASICALLY REACTING NITROGEN ATOM IN PHARMACEUTICALLY ACCEPTABLE ORGANIC SOLVENT SYSTEMS, THE STEP OF INCORPOROUS A SOLUTION AID SELECTED FROM THE GROUP CONSISTING OF ARYL SULFONIC ACID, LOWER ALKYL SUBSTITUTED ARYL SULFONIC ACIDS, HYDROAROMATIC SULFONIC ACIDS, LOWER ALKYL SUBSTITUTED HYDROAROMATIC SULFONIC ACID, TERPENE SULFONIC ACIDS, CAMPHOR SULFONIC ACIDS AND SULFURIC ACID SEMIAMIDES OF THE FORMULA

United States Patent 1970, Ser. No. 9,120

Int. Cl. A611: 9/00 US. Cl. 424-45 20 Claims ABSTRACT OF THE DISCLOSUREA method of forming stable solutions of at least one pharmaceuticalsubstance containing a basically reacting nitrogen atom inpharmaceutically acceptable organic solvent systems, the step ofincorporating a solution aid selected from the group consisting of arylsulfonic acid, lower alkyl substituted aryl sulfonic acids,hydroaromatic sulfonic acids, lower alkyl substituted hydroaromaticsulfonic acid, terpene sulfonic acids, camphor sulfonic acids andsulfuric acid semiamides of the formula wherein R and R takenindividually are hydrogen, lower fsisting of alkylene, aza-alkylene andoxa-alkylene to improve the solubility of the pharmaceutical substancein said solvent system.

This application is a continuation of application Ser. No. 625,322,filed Mar. 23, 1967, now abandoned.

BACKGROUND OF THE INVENTION The present invention relates to a processfor producing improved solutions of basically reacting pharmaceuticalsin pharmaceutically acceptable organic solvents.

The application of pharmaceuticals in the form of injections andaerosols is of considerable significance. Especially, the use ofpharmaceuticals in the form of aersols, for example, for inhalation orlocal applications finds increasing application. These forms of userequire dissolution of the pharmaceutical. Consequently, good solubilityor respectively good solubility promoting agents are a prerequisite foroptimal medical application.

However, the solubility properties of many pharmaceuticals are notsufiicient. Often, for example, the solubility of basic reactingpharmaceuticals in the usual form of their hydrochlorides only sufiicesfor the preparation of pharmaceutically acceptable solutions in water oralcohol. In a number of pharmaceuticals, such as, for example,1-3-methoxy-w-(1-hydroxy 1 phenyl-isopropyl-amino)- propiophenone, N(3-[4-(2-hydroxy-ethyl)-piperazino]- propyl)-2-chloro-thiophenyl pyridylamine, neomycin, aureomycin, papaverine or dl-7-{3-[2-(3,4-dihydroxyphenyl) 2 hydroxy-ethyl-amino]propyl}-theophylline even the solubilityin alcohol is much too low. Furthermore, in many basically reactingpharmaceuticals or their salts the solubilities are entirelyinsufiicient if other organic solvents or organic materials are added totheir aqueous or alcoholic solutions as such additions causeprecipitation of the pharmaceuticals. For instance, the hydrochloridesof pharmaceuticals will precipitate in crystalline form eitherimmediately after or a few minutes 3,816,612 Patented June 11, .1974

ice

2 after ethanol solutions thereof are mixed .withfthepropellant'normally employed for aersols, such as, for example, mayconsist of monofluorotrichloromethane and difluorodichloromethane ordifluorodichloromethane and tetrafluorodichloroethane.

. Investigation of the solubilities of other salts, such as, forexample, the sulfates, phosphates, acetates, propionates, stearates,palmitates, glycolates, tartrates, citrates, lactates, adipates,maleates, fumarates, ascorbates, benzoates and gentisinates showed noimprovements over the hydrochlorides.

SUMMARY OF THE INVENTION According to the invention it was unexpectedlyfound that generally the solubility of pharmaceuticals containing one ormore basically reacting nitrogen atoms in pharmaceutically acceptablesolvents or solvent mixtures can be increased very considerably if arylsulfonic acids, if desired, substituted with lower alkyl groups,hydroaromatic sulfonic acids, if desired, substituted with lower alkylgroups, terpene sulfonic acids, camphor sulfonic acids, guaiazulenesulfonic acid or sulfuric acid semiamides of the formula wherein R and Rtaken individually are hydrogen, phenyl or phenalkyl groups with 1-5carbon atoms in the alkylene group and lower alkyl group and when takentogether are alkylene, oxa-alkylene or aza-alkylene groups forming a 5to 7 membered ring with the nitrogen atom as in pyrrolidine, piperidine,piperazine, homopiperazine and morpholine rings, are employed assolution aids.

Especially suited examples of such sulfonic acids or sulfuric acidsemiamides used as solvent aids according to the invention are benzenesulfonic acids, benzene sulfonic acids substituted with lower alkylgroups, camphor sulfonic acids, guaiazulene sulfonic acid, sulfuric acidmonocycloamides and similar compounds. The solution aids can be usedsingly or in combination.

DETAILED DESCRIPTION OF THE INVENTION INCLUDING PREFERRED EMBODIMENTSThe activity of the sulfonic acids and sulfuric acid semiamidesaccording to the invention in improving the solubility is eifective forall pharmaceuticals which contain one or more basically reactingnitrogen atoms. The chemical structure of the pharmaceutical is oflittle significance and can belong to the most various classes ofchemical substances. For example, it may belong to the class ofB-aminoalcohols and their derivatives, especially, fl-aminoethanols andp-aminopropanols which, if desired, may be substituted by low molecularweight alkyl or aralkyl groups on the amino group and by a phenyl,hydroxy phenyl or dihydroxy phenyl group in a position; or belong to theclass of amino alkyl phenols with alkylene radicals of 24 C atoms; orbelong to the class of diphenyl alkyl amines with alkylene"radicals of2-6C atoms, in which the amino group is substituted with low molecularweight alkyl or aralkyl groups; or belong to the group of basicallysubstituted esters and amides of p-amino benzoic acid in which thehydrogen atoms of the amino group may be substituted by amino alkylgroups and the hydrogen atoms of the amide nitrogen may be substitutedby amino alkyl groups and whereby the alcohol component of the estersis, for example, derived from low molecular weight aliphatic alcohols oraliphatic amino alcohols with 1 to 5 carbon atoms, preferably, from thelower alkanols or lower amino alkanols; or belong to the class ofalkaloids, of tetracyclines of neoe actm g hetero=mycins;on'belong.togtheaclass'of basically r have good solubility inwater. Furthermore, it was found cyclicacompoundsgcontaining, 1 .to,3,.het eroatoms, such,as,.... that solutions of pharmaceuticalsproducedaccording-to oxygen, nitrogen or sulfur, ,which, for example, have a theinvention with, for instance, alcohols can be diluted monocyclic orcondensed bi- -:or tricyclic ring system with considerably with otherorganic solvents before precipitation occurs.

This is illustrated in Table 2 given below which indicates tue ch, ringy stems; if, desired, vcarrying the quantity of other solvent in ml.which can; 'be added halogen v aitorns hydj alkyl, amino or aminolalkylto a solution of the neomycin salt according to the invengroups assubstituent s; or b elongto the. group of basically .tion indicated(corresponding to 330 mg. neomycin base) ubstituted=.-xant l1inegderivatives, especially, theophylline in m1. of ethanol without causingprecipitation.

the .jngliv iti 1 a- 1.ringsheing of 5 ors members and in whichtheubasrc center 1s conta1ned elther 1n .the heterocycle or TABLE 2 v lf Neomycin Neomycin Neomycin Neomycin wherein T'signifies a dialkylxanthine radical, Alk signifies 1 S 1 t P om na cg rpphc nr. llgfinzeieguaiflzfulene an alkylene group (straight or branched) of 2-4 C atoms, 0van 5 9 5 (ma 6 5 9 3 R signifies hydrogen or a lower alkyl group, Rsignifies 10 300 hydrogen or a hydroxy group and R signifies phenyl or55 3y000 a: hydroxy phenyl group. 28 gg g8 3,000 The sulfonic acids andsulfuric acid semiamides employed according to the invention form acidaddition salts with the basically acting pharmaceutical compounds. aTable 1 below illustrates the improved solubilitie b- The improvedsolubilities of salts of various other basic- .tained in various olventsaccording to the invention using ally reactive pharmaceutical compoundsaccording to the neomycin as an, example. All values as to solubilitieshave 25 invention as compared to the solubility of the normal salts beencalculated as neomycin base. such as the hydrochloride is illustrated inTable 3 given TABLE 1 Dissolved quantity neomycin salt, calculated asneomycin-base (mg/500 ml.)

Neomyeiu Neomycin Neomyein Neomycin Neomycin Neomycin p-tolueue camphorbenzene guaiazulene sulfate hydrochloride suh'onate sulionate sulionatesulfonate ca. 10 0 1, 100 1, 100 1, 100 3, 000 PhenoL ca. 10 ca. 10 6,600 6, 600 6, 600 3, 000

The neomycin salts employed according to the invenbelow. The valuesgiven are the quantity of pharmaceutition, for instance, in addition tohaving good solubility in cal calculated as free base in mg. whichdissolve in 6 ml. hydroxyl group containing organic solvents alsogenerally of ethanol (96% TABLE 3 Solution aid, mg.

. Cyclohexy V Hydro- Benzene p-Toluene d,l-Camphor amido- "Basicallyreactive pharmaceutical chloride sulionate sultonate sulionate sulfuricacid 2-methylamlno-1- henyl-propaue-I-ol... l-fime'thoxy-w-(lydroxy-l-phenyiisopropyl-amino)-pr0piophenoue1-l-N-[3-pheuyl-3-hydroxypropyl-(2)]-amlnoethyll-naphthyl-ketone- 2- (p'-hydroxyphenyl) -ethyl ami N-(3,3-di henylpropyD-ti-methylpheuethylaminepallmino nzoie acid-B-diethylamino-ethylester Papgvnrlna :Aureomyein. Yd,l-N-methylhexahydropicolinic-acld-2,6-dimethylanilide2-(morpholi'loethyhnercapto)-6-ch1oropyridine2-(morpholiuoethylsulfoxyl)-6-chloropyridineN-dimethylamlno-isopropyl-thiophenyl-pyridylamine 1 N-(3-Dimethylamiuo-propyl)-thiophenyl-pyridy1amine 1 Nl3-[4-(2-Hydroxy-ethyhiperazinb1-propyll-2-C1-thio henyl-pyridylamine d,l-l-l3'-l2-(3,4-dihydroxy-p enyl) -2-hydroxyethylamino-propyll-theophylline 7-(2-I2-Hydroxy-2-(3,4dihydroxyphenyl)-ethyla.mino]-ethyl]-theophy1line 7-[2-ll-Methyl-Z-phenyl-ethylamino)-ethy11-theophylline An especial advantageof the invention is that it is especially useful in the production ofaerosol preparations. Whereas previously basically. reactingpharmaceuticals often could only be used as suspension aerosols, thepresent invention renders .it possible to. produce such aerosols asclear solutions. Solutions have the advantage over suspensions in thehomogeneous distribution of the pharmaceutical and its uniformapplication. Furthermore, they have the further advantage thatsedimentation or creaming of the solids is avoided and that clogging ofthe "valves and uncertain dosing are precluded.

The solutions produced according to the invention also can containseveral basically acting pharmaceuticals. In addition, other activepharmaceuticals or adjuvants, such as, non-basic pharmaceuticals,stabilizing adjuvants, such as ascorbic acid and its esters, and thelike, taste correcting substances, such as sweetners, aromatic oils,essences and the like, substances which form films on the skin or mucousmembrane, such as polyvinyl pyrrolidone, cellulose derivatives and thelike, local anaesthetics or antihistamines can be incorporated therein.

The following examples will serve to illustrate the invention withreference to several embodiments thereof.

EXAMPLE 1 830 mg. of neomycin d-camphor-B-sulfonate, composed of 330 mg.of neomycin base and 500 mg. of d-camphorp-sulfonic acid, were dissolvedin 25 ml. of benzyl alcohol with light warming and then 25 ml. ofethanol and 5 ml. of isopropyl-myristate were added thereto.Subsequently the solution was mixed with 45 ml. of peanut oil. A clearstable solution resulted.

EXAMPLE 2 415 g. of neomycin benzene sulfonate composed of 165 mg. ofneomycin base and 250 mg. of benzene sulfonic acid were dissolved in g.of polyethylene glycol 400 and then homogeneously mixed with 30 g.pentaerythritolmonolaurate-polyglycol ether and 9.5 g. ofpentaerythritolmonostearate. A hydrophilic salve is obtained whichcontains the antibiotic as a true solution.

EXAMPLE 3 100 mg. of neomycin-guaiazulene sulfonate were dissolved in1.1 ml. of polyethylene glycol 400. This solution was added to a mixtureof 7.2 ml. of pentaerythritolmono-laurate-polyglycol ether and 1.6 ml.of pentaerythritol-monostearate liquified by slight warming whilestirring. After cooling a hydrophilic salve is obtained which containsthe antibiotic as a true solution. This salve is especially interestingin that in addition to the neomycin the guaiazulene component is alsopharmaceutically active.

EXAMPLE 4 106 mg. of neomycin-p-toluene sulfonate composed of 6 acidwere dissolved in a mixture of 30.8 g. of ethanol, 0.9 g. of1,2-propylene glycol and 0.9 g. of fatty alcohol polyglycol ether withslight warming. After cooling'6.3 g. of a copolymer of vinyl pyrrolidoneand vinyl acetate were added to the solution. The solution was thenfilled into an aerosol pressure container provided with a spray valvetogether with 21 g. of difluorodichloromethane-as.propellant. A clearstable solution resulted which could be sprayed without problems.

EXAMPLE 5 106 mg. of neomycin-p-toluene-sulfonate and 194mg.

EXAMPLE 6 96 g. of neomycin-p-toluene sulfonate composed of 38 mg. ofneomycin base and 58 mg. of p-toluene solfonic acid, were dissolvedtogether with 190 mg. of N-dimethylamino isopropyl thiophenylpyridylamine-p-toluenesulfonate in 35 g. of ethanol with slight warming.After cooling, 14 mg. of neomycin-guaiazulene sulfonate and 3.7 g. of acopolymer of vinyl pyrrolidone and vinyl acetate were added to suchsolution and the solution then filled into an aerosol pressure containerprovided with a spray valve together with 21 g. ofdifluorodichloromethane as propellant. A clear stable solution resultedwhich could be sprayed without problems.

EXAMPLE 7 600 mg. of Z-methylamino-l-phenyl-propanol-(1) and 906 mg.d,l-camphor sulfonic acid were dissolved in 96% ethanol with lightheating to a total volume of 6 ml. After cooling, the solution wasfilled together with 10 g. of a mixture of difiuorodichloromethane andtetrafluorodichloroethane 4060 into an aeorsol pressure containerprovided with a spray valve. A clear solution was obtained which couldbe sprayed without problems.

EXAMPLES 8-35 The substances indicated in Table 4 were dissolved, ifnecessary, under slight warming and stirring, and then converted byaddition of fluorohydrocarbons to clear sprayable solutions as describedin Example 7. The volume of the alcoholic active substance solution inExample 10:65 ml., in Example 26:85 ml. and in the remaining Examples=6ml.

In the examples calculated on the amount of fluorochlorohydrocarbonaerosol, the amount of base ranges from a low of 0.2% (Example 4) to ahigh of 12% (Ex- 42 mg. of neomycin base and 64 mg. of p-toluenesulfonic ample 25).

TABLE 4 Example N0. Basic pharmaceutical Mg. Solution aid Mg. Furtheraddition Mg. Propellant G s 1-3-methoxy-w-(1-hy 750 Gyclohexylamldo-Difluorodichloro- 1 droxy-l-phenyl-isosulfuric acid. 432 gg gggg h'methane plus tetrapropyl-ammo)- S nthetic fluorodichloroethanepropiophenone. y 4060. Q do 900 d,l-Qgmpher sulionic 720 do 10Saccharin- 10 10 do 450 Benzene sulfonle acld...... 235 255 22synthetic. Sulfuric acid mono-(N- 0 do 450 cyclohexylamide). 01 Anisl a50 do 10 Benzene sulfonic acid OLOaryophylli 50 121-{N-[3-phenyl-3:hydroxy- 600 d,l-Qamphor sulfonie 450Monofluorotrlchloro- 10 propy1-(2)]-am1no acid. methane plusdifiuoroigliizgllllnaphthyldiehloromethane 5050. 13 Z-(p-hydrOgIyphenyD-600 do e 1,080 do 10 ethy amine. 14 N-(8,3-diphenylpropyl)- 540 n 410 do10 a-methyl-phenethyl- 15 fii b 1 idB 300 die h Ifni 3 pno enzo cae ampor an o c 18 ..:.:.:.:.:;.:.:.;.:.:.:.:.;.;.c..- Difiuorodiehloromethane10 diethylamiuoethylester. 'acid. plus tetrafluorodiehloroethane 4060.

TABLE 4Continued Example N0. Basic pharmaceutical Mg. Solution aid Mg.Further addition Mg. Propellant G 16 Papaverine base 90 6,1 Camphorsulfonic 66 Difiuorodichloromethan'e I acid plus tetrafiuorodiichloroothane 4060;

17 d,l-N-methylhexahydro- 600 p-Toluene sulfonic acid 462 do 10picolinic acid-2,6-dimethyl-anilide.

18 z-(morpholiuoethylmer- 600 Sulfuric acid mono-(N- 414Ascorbylpalmitate 30 do 10 capto)-6-chloropyridine. cyclohexylamide).

19 2-(mor holinoethylsul- 600 d,1-Camphorsu1ionic 546 do 10 foxyl-6-chloropyridine. acid.

20 N-dimethylamino-iso- 600 Sulfuric acid mono-(N- 378 dn 10propyl-thiophenylcyclohexylamide) pyridylamine.

0.6.... 150 p-Toluene sulfonic ac1d.... 215 Polyv1nylpyrro11done.... 500Difiuorodichloromethane. 21 d,1-N-methylhexahydro- 150 picolinieacid-2,6-dimethylanilide.

22 N-(a-dimethylamino- 600 d,1-Camphor sulfonic 498Difluorodichloromethane 10 propyl) -thiophenylacid. plustetrafluorodipyri ylamine. chloroethane 4060.

23 N-(3-[4-(2-hydroxy-ethyD- 600 do 372 1,2-propaned1ol 450 do 10piperaziuol-propyl l-2- Cl-thiophenyl-pyridylamine.

24 2,4-dimethyl-6-sulfanil- 180 do 162 Monofiuorotrichloro- 10ammo-pyrimidine. methane plus difluorodichloromethane 5050.

25 2,6-bis-[di-(fl-hydroxy- 1,200 .do 1,188 do 10ethyl)-amino]-4,8-dlpiperidino-pyrimido- (5,4-d)-pyrimidine.

26 7-{2-[2-hydroxy-2-(3,4-di- 91 p-Toluene sulfomc acid.-. 461,2-pr0paned1ol 400 do 4.5

hydroxyphenyD-ethylfiminolethyll-theophyl- 27 d,1-7-[2-(1-methyl-2-hy-272 d,1-Camphor sultonic 1 0 Difluorodiehloromethane 10droxy-2-phenylethylacid. plustetrafluorodifiminQ-ethyll-theophfichloroethane 4060. I

28 (1,1 -[3-[2-(3,4-dihydroxyd,1-Camphorsu1fonic 20 {1,2-propauedi01.-500 Difluorodichloromethane 10 phenyD-2-hydroxyacid. Ascorbylpalmita 30plus tetrafiuorodiethylaminol-propyllchloroethane 4060. theophylline.

29 7-[2-(1-methyl-2-phenyl- 67.8 p-Toluene sultomc n 37.8 1 fin 10ethylamino)-ethyl]- theophylline.

d,1-7-{-3-g2-(8,4-dihydroxy- 27 d,1-Camphor sulfonic 33.4{1,2-propanedrol.-. 10

phenyl -2-hydroxyacid. Ascorbic acid... ethylaminol-propyll- 30theophylline.

N-dimethylamino-isopropyl-4-azapheno- 18 thiazine.

31 (1,1-7-l3-[2-(3,4-dihydroxy- 30 Sulfuric acid mono-(N- 14.3{1,2-propanediql 500 Monofluorotrichloro- 10phenyD-Z-hydroxycyclohexylamide). Ascorbylpahmtate 30 methane plusditluoroethylamino1-propy1idichloromethane 5050. theophylline.

32 7-[2-(1-methyl-2-phenyl- 67.8 do 35.6 Difiuorodichloromethane 10ethylamino)-ethyl]- plus tetrafluoroditheophylline. chloroethaue 4060.

33 7-2-(l-Methyl-2-phenyl- 67.8 Sulfuric acid mono- 33.2Monofluorotrichloroethylamino)-ethylmorpholide. methane plusdifluorotheophylline. dichloroethane 5050.

84 1-pyrro1idino-4,4-di- 00 p-Toluene sulfonic acid.... 390Difluorodichloromethane 10 phenyl-butin-(2)-ol-(4) plustetrafluorodichloroethane.

35 Aureomycin 150 d,1-Camphorsu1f0n10 78 Monofiuorotrichloro- 10 acid.methane plus difiuorodichloromethane 5050.

We claim:

1. A clear, stable solution under pressure adapted to be dispensed as anaerosol consisting essentially of (l) a pharmaceutical ,B-amino alcohol(2) as a solvent aid therefor a sulfonic acid selected from the groupconsisting of benzene sulfonic acid, toluene sulfonic acid, guaiazulenesulfonic acid, camphor sulfonic acid and sulfuric acid semiamides of theformula alcohol and propellant combination. 75

2. A solution according to claim 1 wherein the p-arninoalcohol is either1,3-methoxy-w-(l-hydroxy-l-phenyl-isopropyl-amino)-propiophenone or1-{N-(3-phenyl-3 hydroxypropyl-(2) )-aminoethyl}-naphthyl ketone.

3. A solution according to claim 1 wherein the propellant has 1 to 2carbon atoms.

4. A solution according to claim 3 wherein the propellant is selectedfrom the group consisting of difluorodichloromethane,tetrafluorodichloroethane and mono-v fluorotrichloromethane.

5. A solution according to claim 1 wherein, in addition to ethylalcohol, there is present in the solution a member of the groupconsisting of ethylene glycol, polyethyelne glycol, propylene glycol,benzyl alcohol and glycerine.

6. A solution according to claim 1 wherein the solution aid is selectedfrom the group consisting of benzene sulfonic acid, p-toluene sulfonicacid, camphor sulfonic acid, guaiazulene sulfonic acid, sulfuric acidmono-(N-cyclohexylamide) and sulfuric acid monomorpholide.

7. A solution according to claim 1 wherein the pharmaceutical substanceis present in an amount of 0.2 to 12% based on the weight of thefluorochlorohydrocarbon. R

8. A clear, stable solution under pressure adapted to be dispensed as anaerosol consisting essentially of (1) a pharmaceutical theophyllinederivative of the formula wherein T is a dialkyl xanthine radical, Alksignifies an alkylene group of 2 to 4 carbon atoms, R is hydrogen or alower alkyl group, R is hydrogen or a hydroxyl group, R is phenyl orhydroxyphenyl, (2) as a solvent aid therefor a sulfonic acid selectedfrom the group consisting of benzene sulfonic acid, toluene sulfonicacid, guaiazulene sulfonic acid, camphor sulfonic acid and sulfuric acidsemiamides of the formula where R and R taken individually are hydrogenor cyclohexyl respectively and R and R taken together is a divalentradical forming a 5 to 6 membered heterocyclic group ring selected fromthe group consisting of pyrrolidine, piperidine, piperazine,homopiperazine and morpholine (3) ethyl alcohol and (4) a fiuorochlorohydrocarbon propellant in an amount sufiicient to enable the solution tobe dispersed as an aerosol, said solution aid increasing the retentionof the pharmaceutical substance in said ethyl alcohol and propellantcombination.

9. A solution according to claim 8 wherein the propellant has 1 to 2carbon atoms.

10. A solution according to claim 9 wherein the propellant is selectedfrom the group consisting of difluorodichloromethane,tetrafluorodichloroethane and monofluorotrichloromethane.

11. A solution according to claim 8 wherein, in addition to ethylalcohol, there is present in the solution a member of the groupconsisting of ethylene glycol, polyethylene glycol, propylene glycol,benzyl alcohol and glycerine.

12. A solution according to claim 8 wherein the solution aid is selectedfrom the group consisting of benzene sulfonic acid, p-toluene sulfonicacid, camphor sulfonic acid, guaiazulene sulfonic acid, sulfuric acidmono-(N- cyclohexylamide) and sulfuric acid monomorpholide.

13. A solution according to claim 8 wherein the pharmaceutical substanceis present in an amount of 0.2 to 12% based on the weight of thefluorochlorohydrocarbon.

14. A clear, stable solution under pressure adapted to be dispensed asan aerosol consisting essentially of 1) a pharmaceutical thiophenylpyridylamine, (2) as a solvent aid therefor a sulfonic acid selectedfrom the group consisting of benzene sulfonic acid, toluene sulfonicacid, guanazulene sulfonic acid, camphor sulfonic acid and sulfuric acidsemiamides of the formula where R and R taken individually are hydrogenor cyclohexyl respectively and R and R taken together is a divalentradical forming a 5 to 6 membered heterocyclic group ring selected fromthe group consisting of pyrrolidine, piperidine, piperazine,homopiperazine and morpholine (3) ethyl alcohol and (4) a fluorochlorohydrocarbon propellant in an amount sufficient to enable the solution tobe dispersed as an aerosol, said solution aid increasing the retentionof the pharmaceutical substance in said ethyl alchol and propellantcombination.

15. A solution according to claim 14 wherein the thiophenyl pyridylamineis N-(3-dimethylamino-propyl) thiophenyl-pyridylamine orN-{3-(4-2-hydroxy-ethyl)-piperazino) -propyl-2-Cl-thiophenyl-pyridylamine.

16A solution according to claim 14 wherein the propellant has 1 to 2carbon atoms.

17. A solution according to claim 16 wherein the propellant is selectedfrom the group consisting of difluorodichloromethane,tetrafluorodichloroethane and monofluorotrichloromethane.

18. A solution according to claim 14 wherein, in addition to ethylalcohol, there is present in the solution a member of the groupconsisting of ethylene glycol, polyethylene glycol, propylene glycol,benzyl alcohol and glycerine.

19. A solution according to claim 14 wherein the solution aid isselected from the group consisting of benzene sulfonic acid, p-toluenesulfonic acid, camphor sulfonic acid, guaiazulene sulfonic acid,sulfuric acid mono-(N- cyclohexylamide) and sulfuric acidmonomorpoholide.

20. A solution according to claim 14 wherein the pharmaceuticalsubstance is present in an amount of 0.2 to 12% based on the Weight ofthe fluorochlorohydrocarbon.

References Cited UNITED STATES PATENTS 2,974,139 3/1961 Schuler et al424246 3,379,650 4/1968 Beasley, Jr. et a1. 252308 2,774,711 12/ 1956Fleischhacker et al. 424-315 3,079,299 2/ 1963 Heilig 424-181 3,141,8217/1964 Compeau 424-315 3,144,386 8/1964 Brightenback 424-45 3,168,562 2/1965 Walton et al 424-326 3,172,816 3/ 1965 Swintosky 424-181 3,174,9053/ 1965 Loo, Jr. et a1 424-181 3,304,230 2/ 1967 Abramson et al. 424-453,322,624 3/ 1967 Stone 424-45 3,322,625 5/1967 Shimmin 424-45 OTHERREFERENCES Surfact Active Agents, vol. I, Schwartz-Perry, IntersciencePubs., Inc., New York (1949), pp. 67, 117-121, 452

and 512.

Chemical Abstracts, vol. 51, pp. 7331-7332, 16567- 16568 (1957).

Chemical Abstracts, vol. 52, p. 17128 (1958). Chemical Abstracts, vol.54, p. 6178 (1960).

ALBERT T. MEYERS, Primary Examiner F. E. WADDELL, Assistant Examiner

